J. Org. Chem., Vol. 44, No. 16, 1979 2941
Notes S-Cyclohexyl 0,O-Dimethyl Phosphorothiolate (1, R = Methyl, R' = Cyclohexyl, Entry 4): bp 64-68 "C (0.02 torr); IR (neat) 1258 (P=O), 1188 (PO) cm-'; 'H NMR (CDCl,) 6 1.04-2.51 (br, 10, CH,), 2.98-3.56 (br, 1, CHS), 3.66, 3.88 (s, 6, CHS). Anal. Calcd for C$I1703PS: C, 42.85; H, 7.64. Found: C, 42.67; H, 8.03. 0,O-Dimethyl 5 4 2 4Methoxycarbonyl)ethyl] Phosphorothiolate (1, R = Me, R' = CH2CH2COOMe,Entry 5): bp 57-62 OC (0.02 torr); IR (neat) 1740 (C==O),1250 (P=O), 1180 (PO) cm-';'H NMR (CDC13)6 2.50-3.50 (m, 4, CH2),3.72 (s, 6, CHS), 3.92 (9, 3, CHS). Anal, Calcd for C$Il3O5PS: C, 31.58; H, 5.74. Found C, 31.11; H, 6.04. 0,O-Dimethyl S-(Ethoxycarbony1)methyl Phosphorothiolate (1,R = Me, R' = CH2COOEt, Entry 6): bp 76-80 "C (0.01 torr) (lit." bp 86 "C (0.05 torr)); IR (neat) 1740 (C=O), 1260 (P=O), 1185 (PO) cm-'; 'H NMR (CDC13)6 1.28 (t,3, CH3),3.45, 3.72 (9, 2 CHZ), 3.72, 3.93 (s, 6, CH3), 4.31 (4,2, CHzS). S-Benzyl 0,O-Diethyl Phosphorothiolate (1, R = Ethyl, R' = Benzyl, Entry 8): bp 110-114 "C (0.02 torr) (lit., bp 129-131.5 "C (0.15 torr)); IR (neat) 3055 (HAr), 1260 (P=O), 1162 (PO) cm-'; 'H NMR (CDCl,) 6 1.30 (t, 6, CH3),3.81-4.40 (m, 6, CH2),7.11-7.53 (m, 5 , HAr). S-Butyl 0,O-Diethyl Phosphorothiolate (1, R = Ethyl, R' = Butyl, Entry 9): bp 35-40 "C (0.01torr) (lit.,' bp 131-133 "C (10 torr)); IR (neat) 1464 (CH,), 1258 (P=O), 1162 (PO) cm-'; 'H NMR (CDCM 6 0.70-1.10 (m. 3. CHd. 1.10-1.93 (m, 4, CH,), 1.33 (t,6, CH,), 5.53-3.10 (m, 2, CH2S),4.07(q, 2, CH'), 4.21 (q, 2, CHJ. S-Cyclohexyl 0,O-Diethyl Phosphorothiolate (1, R = Ethyl, R' = Cyclohexyl, Entry 10): bp 67-70 "C (0.01torr) (lit.23 bp 99-102 "C (0.2 torr));IR (neat) 1249 (P=O), 1155 (PO) cm-'; 'H NMR (CDCI,) 6 1.03-2.20 (br, 10, CH,), 1.36 (t, 6, CH3), 2.93-3.58 (br, 1, CHS), 4.09 (4,2, CH2),4.23 (q, 2, CH,). 0,O-Diethyl S-[2-(Methoxycarbonyl)ethyl] Phosphorothiolate (1, R = Et, R' = CH2CH,COOMe, Entry 11): bp 67-70 "C (0.02 torr) (lit.24bp 137 "C (3.0 torr)); IR (neat) 1738 (C=O), 1248 (P=O), 1160 (PO) cm-'; 'H NMR (CDC13)6 1.36 (t,6, CHJ, 2.50-3.40 (m, 4, CHJ, 3.70 (s, 3, CHJ, 4.09 (4, 2, CHJ, 4.24 (4,2, CH,). 0 , O-Diethyl S-(Ethoxycarbony1)methyl Phosphorothiolate (1, R = Et, R' = CH&OOEt, Entry 12): bp 70-75 "C (0.005 torr) (lit.%bD 78-81 "c (0.01torr)): IR (neat) 1738 (c=o). 1258 (P=Oj, 1160'(PO) cm-'; 'H NMR (CDCl,) 6 1.12-1.58 (m, 9, CH,), 3.45, 3.70 (s, 2, CH'S), 3.92-4.49 (m, 6, CHJ. 0,O-Diisopropyl S-Phenyl Phosphorothiolate ( l,I9 R = Isopropyl, R' = Phenyl, Entry 13): bp 88-92 "C (0.02 torr); IR (neat) 3048 (HAr), 1388, 1378, 1256 (P=O) cm-'; 'H NMR (CDCl,) 6 1.24,1.34 (dd, 12, CH3),4.48-5.04 (m, 2, CH), 7.26-7.66 (m, 5, HAr). S-Benzyl 0,O-Diisopropyl Phosphorothiolate (1, R = Isopropyl, R' = Benzyl, Entry 14): bp 90-95 "C (0.01 torr) (lit.% bp 126 "C (0.04 torr)); IR (neat) 3056 (HAr), 1390, 1380, 1258 (P=O) cm-'; 'H NMR (CDC1,) 6 1.26, 1.36 (dd, 12, CH,), 3.96, 4.17 (9, 2, CH,), 4.41-4.97 (m, 2, CH2),7.10-7.50 (m, 5 , HAr). S-Cyclohexyl 0,O-Diisopropyl Phosphorothiolate (1, R = Isopropyl, R' = Cyclohexyl, Entry 15): bp 60-65 "C (0.005 torr); IR (neat) 1452 (CHJ, 1386,1376,1246( P 4 ) cm-'; 'H NMR (CDClJ 6 0.95-2.35 (br, 10, CHJ, 1.28, 1.38 (dd, 12, CH3),2.95-3.53 (br, 1, CHS), 4.43-4.99 (m, 2, CH). Anal. Calcd for Cl2HZ5O3PS:C, 51.41; H, 8.99. Found: C, 51.12; H, 9.08. 0,O-Diphenyl S-Phenyl Phosphorothiolate (1, R =
Phenyl, R' = Phenyl, Entry 16): bp 106-110 "C (0.02 torr); IR (neat) 3048 (HAr), 1274 (P=O), 1190 (PO) cm-'; 'H NMR (CDClJ 6 6.95-7.65 (m, 15, HAr). Anal, Calcd for CI8Hl5O3PS: C, 63.15; H, 4.42. Found: C, 63.16; H, 4.49. S-Benzyl 0,O-Diphenyl Phosphorothiolate (1, R = Phenyl, R' = Benzyl, Entry 17): mp 64-66 "C (lit. mp 65-67 "C); IR (Nujol) 3040 (HAr), 1278 (P=O), 1194 (PO) cm-'; 'H NMR (CDC1,) 6 4.03, 4.25 (s, 2, CH,), 7.07-7.40 (m, 15, HAr). S-Cyclohexyl 0,O-Diphenyl Phosphorothiolate (1, R = Phenyl, R' = Cyclohexyl, Entry 18): bp 102-105 "C (0.01 torr); IR (neat) 3050 (HAr), 1485 (CHJ, 1262 (P=O), 1190 (PO) cm-'; 'H NMR (CDClJ 6 1.W1.40 (br, 10, CHJ, 3.10-3.80 (br, 1,CHS), 7.30 (br, s, 10, HAr). Anal. Calcd for Cl8Hz1O3PS:C, 62.06: H, 6.08. Found: C, 62.03; H, 6.36. Electrolysis of 3 ( R = Phenyl) and NaBr in MeCN. A mixture of 3 (R' = phenyl, 218 mg, 1 mmol) and NaBr (129 mg, 1.25 mmol) in MeCN (20 mL) containing Et4NC104(100 mg) was electrolyzed at 3 V (applied voltage), 4-3 mA/cm2, at 29-30 "C faraday of electricity was passed and for 2.5 h. After 2 X the solvent was removed, chromatography (SiO?,hexanelbenzene) gave 4 (R' = phenyl, 11 mg, 4%) and recovered 3 (195 mg, 89%). Electrolysis of 2 (R = Et) and NaBr in MeCN. A mixture of 2 (R = Et, 141 mg, 1 mmol) and NaBr (129 mg, 1.25 mmol), in MeCN (20 mL), was electrolyzed at 3 V (applied voltage), 1.4-1 faraday of electricity mA/cm2, at 27-28 "C for 6 h. After 1 X was passed and the solvent was removed, chromatography (SiO,, CHC13/AcOEt)gave 5 (R = Et, 63 mg) and recovered 2 (37 mg). IR and 'H NMR spectra of 5 were identical with those of authentic sample. Electrolysis of a Mixture of 2 and 3 without Using Halide Salts. A solution of 2 (R = Et, 320 mg, 2.3 mmol) and 3 (R' = phenyl, 222 mg, 1 mmol) in MeCN (20 mL) containing Et4NC104 (100 mg) was electrolyzed at a constant voltage of 3 V (anode potential 1.0-1.2 V vs. Ag/AgC104), giving 2.8-0.1 mA/cm2, at 19-25 "C. After passage of 3.5 X IO-, faraday of electricity during 60 h, the mixture was concentrated in vacuo and the residue was chromatographed (SiOz,hexane/benzene/AcOEt) to give 1 (R = Et, R = phenyl, 117 mg, 23%),2 (117 mg, 37%),3 (19 mg, 9%), and 4 (R' = phenyl, 54 mg, 22%).
(21) Nguyen-Thanh-ThuongFrench Patent 1450400 (Cl. C 07f, A O l N ) , 1966; Chem. Abstr. 1967, 66, 94695. (22) Petrov, K. A,; Bliznyuk, N. K.; Mansurov, I. Yu. USSR Patent, 130156, 1960; Chem. Abstr. 1961,55,63745. 123) R. Swiss Patent 323228 (C1. 360). , ~Sallmann. .~.~~ ~ , . , 1957:, Chem. Abstr. 1958,52, 14959d.~ (24) Arbuzov, B.A.; Ymukhametova,D. Kh. Izut. Akad. Nauk SSSR, Otd. Khim. Nauk 1960, 1881; Chem. Abstr. 1961,55, 16410g. (25) Schlor,H.; Schrader, G. German Patent 1083 809 (Cl. 12o), 1960; Chem. Abstr. 1961, 55, 17500~. (26) Kado, M . Yuki Gosei Kagaku Kyokai Shi 1971,29, 197; Chem. Abstr. 1972, 76, 21819.
Received J a n u a r y 25, 1979
~~~
~~~~
~
0022-3263/79/1944-2941$01.00/0
Registry No. 1 (R = Me, R' = phenyl), 4237-00-7;1 (R = Me, R' = benzyl), 7205-16-5; 1 (R = Me, R' = butyl), 26901-83-7;1 (R = Me, R' = cyclohexyl), 70550-08-2;1 (R = Me, R' = CH,CH,COOMe), 70550-09-3;1 (R = Me, R' = CH,COOEt), 2088-72-4;1 (R = Et, R' = phenyl), 1889-58-3;1 (R = Et, R' = benzyl), 13286-32-3;1 (R = Et, R' = butyl), 20195-07-7;1 (R = Et, R' = cyclohexyl),26437-23-0; 1 (R = Et, R' = CH2CH2COOMe),70550-10-6; 1 (R = Et, R' = CH,COOEt), 2425-25-4; 1 (R = isopropyl, R' = phenyl), 15267-38-6; 1 (R = isopropyl, R' = benzyl),26087-47-8;1 (R = isopropyl, R' = cyclohexyl),70550-11-7;1 (R = phenyl, R' = phenyl), 70562-38-8;1 (R = phenyl, R' = benzyl), 13879-47-5;1 (R = phenyl, R' = cyclohexyl), 70550-12-8;2 (R = Me), 868-85-9; 2 (R = Et), 762-04-9; 2 (R = isopropyl), 1809-20-7;2 (R = phenyl), 4712-55-4;3 (R' = phenyl), 882-33-7;3 (R' = benzyl), 150-60-7;3 (R' = butyl), 629-45-8;3 (R' = cyclohexyl),2550-40-5;3 (R' = (CH,),COOMe), 15441-06-2;3 (R' = CH2COOEt),1665-65-2;4 (R' = phenyl), 1212-08-4;5 (R = Et), 107-49-3.
Convenient Synthesis of g-Methylbenzo[ alpyrene' John W. Lyga and John A. Secrist III* T h e Ohio S t a t e University, Department of Chemistry, Columbus, Ohio 43210
In connection with some studies concerning the diol epoxide mechanism of carcinogenesis for polycyclic aromatic hydrocarbons, we required a convenient synthesis (1) In the earlier literature, this is referred to as 2'-methyl-3,4-benzpyrene; see "The Ring Index", 2nd Ed.; The American Chemical Society: Washington D.C.; 1960, p 922, entry 6399 for the presently accepted
numbering.
0 1979 American Chemical Society
2942 J. Org. Chem., Vol. 44, No. 16, 1979
Notes
of 9-methylbenzo[a]pyrene (1) by way of its known preExperimental Section cursor 7-keto-9-methyl-7,8,9,lO-tetrahydrobenzo[a]pyrene I-Formylpyrene (3b). The literature procedure5was followed (2). T h e only literalture procedure leading to l 2requires except that the solvent (dichlorobenzene) was deleted. From 50 g of pyrene, 44.5 g (78%) of 3b was obtained after recrystallization from 95% ethanol, mp 125-126 "C (lit. mp 126 OC5). 2-(Methy1thio)-1-(1-pyreny1)-I-propene(3c). To a solution of 14.6 g (0.069 mol) of diethyl 1-(methylthio)ethylphosphonates in 300 mL of THF at -70 "C under nitrogen was added 31.5 mL (0.063 mol) of 2 M n-BuLi in hexane over 15 min. After stirring 7 6 5 3-4 h, 14.4 g (0.063 mol) of 3b in 100 mL of THF was added over I/ 30 min. The resulting solution was stirred for 30 min at -70 "C, 3 1 and allowed to warm up to room temperature. After addition 2 of 200 mL of saturated NH,Cl, the mixture was extracted with 1:l ether-benzene (2 x 100 mL). The organic extracts were washed with saturated NaHC03 solution (100 mL) and saturated NaCl(100 mL) and gravity filtered through a cone of anhydrous MgS04. Removal of solvent under reduced pressure left ca. 20 g of crude yellow 3c, sufficiently pure for the next step. Analytically pure material was produced by recrystallization twice 3 from acetone: mp 95.5-96 "C; 'H NMR (CDCl,) 6 1.90 (d, J = a, R = H d, R = CH,COCH, 1 Hz, 3, CH3C=C), 2.35 (s, 3, CH3S), 6.63 (br s, 1, CH=C), b, R = CHO e, R = CH,C(CH,)= 7.52-8.10 (m, 9, ArH); exact mass calcd m / e 288.0973, found c, R = CH=C(SCH, )CH, CHCO,CH,CH, 288.0981. f, R = CH,CH( CH,)CH,CO,H Anal. Calcd for CZ0Hl6S:C, 83.29; H, 5.59. Found: C, 83.05; H, 5.60. 13 steps from pyrene and is quite laborious. We have l-(l-Pyrenyl)-2-propanone(3d). A solution of 20 g (0.069 developed a seven step synthesis of 2 from pyrene (going mol, used directly) of crude 3c in 550 mL of 3.5:1:1 acetonethrough several of the same intermediates) which improves HzO-acetonitrile was heated a t reflux for 36 h, decolorized, and the overall yield and which also should prove useful for filtered through Celite. The solution was neutralized with the synthesis of other substituted polycyclic aromatic saturated NaHC03 (100 mL), concentrated, and extracted with 1:l ether-benzene (2 X 100 mL). The organic extracts were hydrocarbons. washed with 1 N aqueous KI (100 mL) and saturated NaHC03 T h e simplest approach to attaching the 9-methylated (100 mL), then gravity filtered through a cone of anhydrous benzo ring to pyrene (3a) would employ a standard MgSO,. Removal of solvent in vacuo left a yellow solid which Friedel-Crafts strategy utilizing methylsuccinic anhydride. was recrystallized from ether to yield 9.2 g (68% from 3b) of 3d; However, this provided exclusively the isomer leading to 'H NMR (CDC13) 6 1.98 (5, 3, CH3), 4.15 (s, 2, CHZ), 7.55-8.11 8-methylbenzo[~]pyreene.~Our approach was to utilize two (m, 9, aromatic);exact mass calcd m / e 258.1045, found 258.1050. successive condensation reactions, each incorporating two Anal. Calcd for CI9Hl40: C, 88.34; H, 5.46. Found: C, 88.18; carbons, to build up the required five carbons unambigH, 5.43. uously from 1-formylpyrene (3b).4 (2)and (E)-Ethyl 3-Methyl-4-(l-pyrenyl)-2-butenoate (3e). To 31.2 g (0.172 mol) of dicyclohexylamine in 500 mL of T h e preparation of 3b was accomplished with a subTHF under Nz at -70 "C was added 82 mL (0.172 mol) of 2.1 N stantial increase in yield simply by omitting the solvent n-butyllithium in hexane over 10 min. The solution was stirred from the standard Vilsmeier-Haack condition^.^ Confor 15 min, and 27.5 g (0.172 mol) of ethyl trimethyl~ilylacetate~ densation of 3b with diethyl (1-methy1thio)ethylin 200 mL of THF was added over 15 min. After a total of 30 phosphonate6 produced the vinyl sulfide 3c, which was min, 22.2 g (0.086 mol) of 3d in 350 mL of THF was added over readily hydrolyzed with mercuric ion to the ketone 3d 30 min. The cloudy yellow solution (deep red in some runs where (68% overall yield from 3b).7 T h e last two carbons were 3d was not rigorously purified) was stirred a t -70 "C for 1 h, and incorporated by treatment of 3d with the anion derived then allowed to warm to room temperature. The solution was from ethyl trimethy Isilylacetateg to produce the a,p-unquenched with 150 mL of saturated NH4Cl and 150 mL of 1 N HCl, and filtered through Celite to remove the amine hydrosaturated ester 3e in 80% yield.'O Saponification of 3e chloride. After concentration to remove THF, the aqueous followed by catalytic hydrogenation afforded 3-methylsolution was extracted with 1:l ether-benzene (2 X 75 mL). The 4-(l-pyrenyl)butanoic acid (3f),which was converted to organic extracts were washed with 1 N HC1 (100 mL), saturated the acid chloride with PCl, and cyclized to 2 with SnC14.2 NH4Cl,and saturated NaCl, and gravity filtered through a cone Conversion of 2 to 1 was accomplished in much improved of anhydrous MgS0, and charcoal. Removal of solvent left a pale yield by reduction with NaBH, and aromatization with green-yellow oil which was of sufficient purity to carry on to the palladium on charcoaL2 next step (22.7 g, 80%). An analytical sample of the mixture was prepared by preparative TLC (silica gel, elution with 1:4 ether-petroleum ether) followed by molecular distillation [165 "C (0.02 mm)]. Partial isomer separation was possible with repeated (2) Bachmann, W. E.; Carmack, M. J . Am. Chem. SOC.1941, 63, 2494-2499. elutions: 'H NMR (CDCl,) more polar isomer, 6 1.26 (t, 3, (3) Winterstein, A.; Vetter, H.; Schon, K. Chem. Eer. 1935,68,1079-1085. OCHZCHJ, 2.31 (d, 3, J < 1Hz, CH,C=C), 4.09 (q,2,OCHZCHJ, (4) Approaches incorporating all four carbons at once, for example with 4.41 (s, 2, CCH,C), 5.50 (m, 1,CH=C), 7.75-8.35 (m, 9, aromatic); a Grienard reagent. did not work. less polar isomer 6 1.35 (t, 3, OCH,CH,), 1.70 (d, 3, J = 1.5 Hz, (5jVollmani, H:;Becker, H.; Corell, M.; Streeck, H. Justus Liebigs CH3C=C), 4.33 (4,2, OCHzCH3),4.80 (s, 2, CCHzC),5.91 (m, 1, Ann. Chem. 1937,531, 1-159. (6) Corey, E. J.; Shulman, J. I. J. Org. Chem. 1970, 35, 777-780. (7) The carbanion derived from (a-chloroethv1)trimethvlsilaneis a recently developed reagent which can be used for tGs reductive-nucleophilic acylation.8 In our hands the yields for this procedure were significantly poorer than with the phosphonate reagent. (8) Cooke, F.; Magnus, P. J . Chem. SOC.,Chem. Commun. 1977,513. (9) Shimoji, K.; Taguchi, H.; Yamamoto, H.; Nozaki, H. J. Am. Chem. SOC.1974, 96,1620-1621. (10) (Carbomethoxymethyl)triphenylphosphorane, the anion derived from dimethyl(carbomethoxymethyl)phosphonate, and lithium tertbutylacetate all afforded inferior yields of product.
(11) Melting points were determined on a Thomas-Hoover capillary melting-point apparatus and are corrected. 'HNMR spectra were measured with a Varian EM-360 instrument; chemical shifts are expressed in parts per million downfield from internal tetramethylsilane. Mass spectra were recorded with an AEI-MS9 spectrometer at 70 eV. Microanalyses were done by Galbraith Laboratories, Inc. Tetrahydrofuran was dried by distillation from sodium and benzophenone or calcium hydride. The ultraviolet absorption spectrum (in nm) was recorded on a Cary 15 ultraviolet absorption spectrophotometer.
J. Org. Chem., Vol. 44, No. 16, 1979 2943
Notes CH=C), 7.80-8.45 (m, 9, aromatic); exact mass calcd m/e 328.1464,found 328.1468. Anal. Calcd for C23H2002: C, 84.12;H, 6.14. Found: C, 83.85; H, 5.89. 3-Methyl-4-(l-pyrenyl)butanoic Acid (30. A mixture of 19.5 g (59.3mmol) of 3e, 150 mL of 40% aqueous KOH, and 50 mL of ethanol was heated at reflux for 3 h (alcoholic KOH is equally acceptable), cooled, and acidified with 6 N HC1. The precipitate was filtered off and recrystallized from benzene-ether to yield 16.0g (89%) of the cr,P-unsaturated acids (30. A solution of 11.16 g (36.9mmol) of 3f and 1.7g of 10% Pd/C in 150 mL of 9 1 ethyl acetate-acetic acid was hydrogenated (Parr shaker) at 3.5 atm for 24 h. Removal of catalyst by filtration and solvent under reduced pressure followed by recrystallization of the residue from benzene-petroleum ether afforded 9.9 g (87%) of 3g: mp 124-129 "C (lit. mp 125-135 "C'); exact mass calcd m / e 302.1307,found 302.1314. g-Methylbenzo[ alpyrene (1). The conversion of 3f to 2 was accomplished as described2in 93% yield, mp 175.5-176 "C (lit. mp 176.5-177.5 "C2). To ketone 2 (7.0 g, 24.6 mmol) in 300 mL of 1:l THF-ethanol was added 0.6 g (15.8mmol) of NaBH, in three portions. After 20 h, hydrolysis was accomplished with saturated NH4C1,and the solution was concentrated. Extraction with 1:l ether-benzene (2 x 100 mL) followed by washing the organic extracts with saturated NaCl, decolorization, gravity filtration through a cone of MgS04,and evaporation of the solvent afforded a yellow solid (one spot by TLC) which was used directly (4.79g, 68%). Aromatization was accomplished as described2with 10% Pd/C (25% by weight), purifying by vacuum distillation directly from the reaction mixture followed by recrystallization from benzene-methanol. From 0.32g of alcohol, 0.23 g of 1 was isolated (77%): mp 139-140 "C (lit. mp 139-140 "C2);'H NMR (CDCl,) 6 2.62 (5, 3, CH,), 7.08,7.34,7.48,7.72,7.88,7.97,8.03, 8.13,8.22,8.58,8.70,8.87(m, 11,aromatics);UV (EtOH) A,, (e) 407 (6400),386 (20800),384 (20300),379 (26200),367 (20500), 350 sh (11300),335 sh (5200), 298 (57200),286 (44200),273 (30500),267 (48900),256 (37700),228 (24700),222 (23100). Registry No. 1, 70644-19-8; 2, 70644-20-1;3a, 129-00-0;3b, (Z)-3e, 3029-19-4; 312,70644-21-2; 3d,70644-22-3; (E)-3e, 70644-23-4; 70644-24-5;3f, 70644-25-6;7-hydroxy-9-methyl-7,8,9,lO-tetrahydrobenzo[a]pyrene, 70644-26-7;diethyl 1-(methy1thio)ethylphosphonate, 22966-40-1; ethyl trimethylsilylacetate, 4071-88-9.
Stereospecific Synthesis of threo- and erythro - 1- (Aryloxy)-3-(alkylamino)butan-2-01s Howard Tucker Imperial Chemical Industries Limited, Pharmaceuticals Division, Mereside Alderley Park, Macclesfield Cheshire, England SKlO 4TG Received December 11, 1978 There is an extensive literature on the biological consequences of a-alkyl substitution in the ethanolamine moiety of P stimulants related to isoproterenol1 and related P a n t a g o n i s k 2 By contrast, relatively little structureactivity work has been reported on the effects of a-alkyl substitution on the biological properties of the medicinally important P antagonists related to propranolol (1). In
d y OH
NHPr'
ArO
Scheme I H
3, threo, R , = H, R, = Me 4, erythro, R , = Me, R, = H
1
5
6, R , = H, R, = Me 7, R , = Me, R, = H
8 , threo, R , = H, R, = Me 9, erythro, R , = Me, R, = H
studying this problem we devised a route for the stereoselective synthesis of the threo and erythro isomers of l-(aryloxy)-3-(alkylamino)butan-2-ols (2) starting from the simple precursors cis- and trans-crotyl alcohol. Recent reports on the synthesis of a- and y-methyl(ary1oxy)pro pa no la mine^^,^ have prompted us t o report our own findings. We discovered that phenols reacted with both threo- and erythro-(l-brom6ethyl)oxirane5 (3 and 4, respectively) under basic conditions a t room temperature to give in each case a single oxirane product to which we have assigned the cis and trans structures 6 and 7 (see reaction Scheme I). T h e threo-(1-bromoethy1)oxirane(3) was prepared from trans-crotyl alcohol as described by Hiskey e t a1.;6 the erythro isomer (4)was obtained from cis-crotyl alcohol by an analogous method. I n practice, 3 and 4 are considerably less reactive than the related demethyl analogue chloromethyloxirane, and there is still ca. 10% phenol present after 3 days' stirring. We usually stopped the reaction a t this stage and the excess phenol was easily removed by extraction with dilute caustic soda. In principle the reaction of oxirane 3 with a nucleophile can occur a t carbon atoms 1, 2, or 3. Attack a t carbon 2 was ruled out since this could not yield an oxirane and moreover there is ample precedent' t h a t nucleophiles attack oxiranes a t the least substituted carbon atom. A direct SN2attack on carbon 3 with displacement of t h e bromine atom would have given a terminal oxirane whereas the 'H N M R spectra of the products 6a-c clearly show signals for two vicinal oxirane protons and for the OCHz group. Attack a t carbon 1 is consistent with the findings of Hiskey e t a1.,6 who showed t h a t 3 reacted with sodium acetylide at carbon 1, and also of Waters e t al.,* who showed t h a t sodium methoxide attacked (l-bromoethy1)oxirane a t carbon 1. Interestingly Waters e t al.
qNHR OH
2
1 (1) R.T.Brittain, D. Jack, and A. C. Ritchie, Adu. Drug Res., 5, 197 (1970). (2)R. Howe, J.Med. Chem., 12,642(1969),and references cited therein.
0022-3263/79/1944-2943$01.00/0
(3) G. Shtacher, R. Rubenstein, and P. Somani, J. Med. Chem., 21,678 (1978). (4)T.L.Lemke, R. L. Boblitt, G. A. Capiton, L. A. Cates, and G. E. Martin, J. Org. Chem., 43, 2079 (1978). (5)A more precise nomenclature for threo-(1-bromoethy1)oxirane(3) is 2(SR)-[ 1(SR)-bromoethylloxiraneand likewise the erythro isomer (4) is 2(SR)-[l(RS)-bromoethyl]oxirane. (6) C. F. Hiskey, H. L. Slates, and N. L. Wendler, J . Org. Chem., 21, 429 (1956). (7) R. E.Parker and N. S. Isaacs, Chem. Reu., 59,737 (1959). (8)R.C. Waters and C. A. Van Der Werf, J . Am. Chem. SOC., 76, 709 (1954).
0 1979 American Chemical Society
